The candidate, Dr. Shirley B. Shelton, has nine years of experience as a practicing and teaching veterinary neurologist and six years of basic research experience during her combined doctoral and postdoctoral training and has almost completed her first year in the Crutcher lab. The focus of her doctoral research was the role of tau phosphorylation in neuronal apoptosis. Her special interest is in neuropathology and her long- term goal is to develop an optimal animal model of neurodegeneration. In November 2003, she joined the laboratory of Dr. Keith Crutcher at the University of Cincinnati. Dr. Crutcher's has been an exceptional mentor for Dr. Shelton and will guide her into maturing as a successful, independent scientist. His group has published several papers on the neurotoxicity of apolipoprotein E4 (E4). Both E4 and traumatic brain injury (TBI) are major risk factors for the most common neurodegenerative disorder, Alzheimer disease (AD). The working hypothesis of this proposal is that proteolysis of E4 contributes to the neuropathology of AD and that this proteolysis may be a downstream event secondary to an elicitor of the inflammatory response, such as TBI. Dr. Crutcher's laboratory has shown that a truncated fragment of apoE (t-apoE) is abundant in AD brain and that t-apoE exhibits neurotoxicity in vitro. In the first aim, knock-in human apoE mice will be used as survival models of TBI. Dr. Kenneth Strauss, the secondary mentor, has provided guidance in the TBI model. Following TBI, the mice are being examined with a combination of methodologies to detect the presence of t- apoE and to study the overall effects of the apoE genotype on TBI. Both the acute and long-term effects of TBI on these transgenic mice are to be examined. Aim 2 will involve a gene replacement strategy to generate mice that overexpress truncated t-E4, t-E3 or t-E2. These mice will provide further information of the neurotoxicity of t-E4. Overall, this environment is an exceptional opportunity for training with animal models in biomedical research.